Asthma and airway inflammatory disease has become the leading cause for ER visits in the US, a four- decade trend linked to the increasing sterility of western lifestyles and a proposed lack of early microbial antigen exposure. Gastrointestinal contact with the Bacteroides fragilis glycoantigen (GlyAg) polysaccharide A (PSA) has been shown to educate the immune system to limit the degree of inflammation in the gut. Effective immune responses upon re-exposure to an antigen is typically mediated through antigen-experienced memory T cells, whereas regulatory T (Treg) cells are known to play key roles in suppressing immune responses, generally through the secretion of immunosuppressive cytokines like IL-10. Our preliminary data show that gut exposure to PSA increases a population of antigen experienced CD4+CD45RbloTEM cells which are capable of amplifying IL-10 production in peripheral tissues upon inflammatory stimulus. Additional data demonstrates that these CD45RbloTEM cells synergistically induce IL-10 production with Tregs when co-cultured in vitro. We hypothesize that commensal microflora are linked to peripheral immunomodulation through T-cell cooperation between commensal-specific CD45RbloTEM cells and tissue-resident Tregs. In this proposal, we will (1) identify the mediator(s) by which this novel pathway of T cell T cell cooperation is capable of dampening the magnitude of antigen-specific memory responses in the periphery, and (2) establish proof-of-principle pre-clinical applications of this pathway to ameliorate experimental airway inflammation. This study will provide a novel mechanistic framework for the hygiene hypothesis, whereby communication between the microbiota in the gut and the T cell compartment links commensal products to non-specific peripheral immune quiescence resulting in reduced susceptibility to inflammation. Dissecting this process will provide a basis for the treatment of inflammatory disease and autoimmunity with oral delivery of specific bacterial glycoantigens, and may provide new T cell directed therapeutic targets for the treatment of these diseases.